Structure and regulation of the Myotonic dystrophy kinase-Related Cdc42-binding Kinase

Truebestein, L.; Waltenberger, E.; Gehin, C.; Gavin, A.-C.; Leonard, T. A.

doi:10.1101/2022.03.11.483953

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bioRxiv · 10.1101/2022.03.11.483953

Structure and regulation of the Myotonic dystrophy kinase-Related Cdc42-binding Kinase

Truebestein, L.·Waltenberger, E.·Gehin, C.·Gavin, A.-C.·Leonard, T. A.

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Abstract

Remodeling of the cytoskeleton underlies myriad processes essential for life. Protein kinases of the DMPK family are critical regulators of actomyosin contractility in cells. In the nematode worm, Caenorhabditis elegans, MRCK1 is required for the activation of myosin, leading to the development of cortical tension, apical constriction and early gastrulation. Here, we present the structure, conformation, and membrane-binding properties of C. elegans MRCK1. MRCK1 forms an obligate homodimer with N-terminal kinase domains, a parallel coiled-coil of 55 nm, and a C-terminal tripartite module of C1, PH and CNH domains. High-throughput liposome binding assays indicate binding to specific phosphoinositides, while the C-terminal Cdc42-binding (CRIB) motif binds specifically to activated Cdc42. The length of the coiled-coil domain of MRCK, as well as those of the related DMPK kinases ROCK, CRIK and DMPK, is remarkably conserved over millions of years of evolution, suggesting that they may function as molecular rulers to precisely position kinase activity at a fixed distance from the membrane.

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Truebestein, L., Waltenberger, E., Gehin, C., Gavin, A.-C., Leonard, T. A.. 2022-03-11. Structure and regulation of the Myotonic dystrophy kinase-Related Cdc42-binding Kinase. https://doi.org/10.1101/2022.03.11.483953

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